"Genetics and Genomics in Medicine is a new textbook written for undergraduate and graduate students, as well as medical researchers, which explains the science behind the uses of genetics and genomics in medicine today. It is not just about rare inherited and chromosomal disorders, but how genetics affects the whole spectrum of human health and disease. DNA technologies are explained, with emphasis on the modern techniques that have revolutionized the use of genetic information in medicine and are indicating the role of genetics in common complex diseases. The detailed, integrative coverage of genetic approaches to treatment and prevention includes pharmacogenomics and the prospects for personalized medicine. Cancers are essentially genetic diseases and are given a dedicated chapter that includes new insights from cancer genome sequencing. Clinical disorders are covered throughout and there are extensive end-of-chapter questions and problems"--Provided by publisher.

OBJECTIVE: Genomics Quality Assessment has provided external quality assessments (EQAs) for preimplantation genetic testing (PGT) for 12 years for eight monogenic diseases to identify sub-optimal PGT strategies, testing and reporting of results, which can be shared with the genomics community to aid optimised standards of PGT services for couples. METHOD: The EQAs were provided in two stages to mimic end-to-end protocols. Stage 1 involved DNA feasibility testing of a couple undergoing PGT and affected proband. Participants were required to report genotyping results and outline their embryo testing strategy. Lymphoblasts were distributed for mock embryo testing for stage 2. Submitted clinical reports and haplotyping results were assessed against peer-ratified criteria. Performance was monitored to identify poor performance. RESULTS: The most common testing methodology was short tandem repeat linkage analysis (59%); however, the adoption of single nucleotide polymorphism-based platforms was observed and a move from blastomere to trophectoderm testing. There was a variation in testing strategies, assigning marker informativity and understanding test limitations, some clinically unsafe. Critical errors were reported for genotyping and interpretation. CONCLUSION: EQA provides an overview of the standard of preimplantation genetic testing-M clinical testing and identifies areas of improvement for accurate detection of high-risk embryos.

• MeSH
• aneuploidie MeSH
• blastocysta MeSH
• genetické testování metody   MeSH
• lidé MeSH
• preimplantační diagnóza * metody   MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Primární imunodeficience (PID) je skupina geneticky podmíněných poruch imunitního systému, u které již bylo popsáno více než 300 kauzálních mutací. Negativním prognostickým faktorem pacientů s PID je tzv. dysregulace imunitního systému, projevující se autoreaktivními a autoinflamatorními komplikacemi. Zavedením sekvenování nové generace do klinického hodnocení je rychle rozšiřován rozsah monogenních poruch odpovědných za rozvoj PID. Značná část takto nalezených genetických variant ale není popsána v literatuře ani v dostupných databázích, a je proto bez předchozího testování nemožné posoudit jejich vliv na patogenezi a progresi onemocnění. Proto navrhujeme vyvinout a zavést do klinického hodnocení i metody podrobné imunofenotypizace leukocytů, doplněné o funkční hodnocení jejich reakcí na ex vivo stimuly. Souběžně budeme sekvenovat repertoár T a B buněčných receptorů pro identifikaci jejich restrikce, která se může podílet na projevech dysregulace. Souhrnné poznatky o změnách ve fenotypu, signalizaci a imunitním repertoáru pomůžou vybrat a v čase monitorovat vhodnou léčbu PID.; Primary Immunodeficiency Diseases (PIDD) are a group of disorders of the immune system, with over 300 causal mutations described to date. Immune dysregulation manifesting as autoimmunity and autoinflammation was described as a negative prognostic factor for patients with PIDD. Implementation of next generation sequencing into the clinical evaluation of affected individuals widens the range of identified monogenic errors rapidly. However, uncovering new variants previously undescribed in the literature and available databases makes impossible to assess their impact on the pathogenesis and progression of the disease. Therefore we propose to develop and implement methods for detailed immunophenotypic description of leukocytes, complemented with functional assessment of responses to ex vivo stimuli. In parallel, we will sequence a repertoire of T cell and B cell receptors in search for skewed patterns explaining deficiency and dysregulation. These insights into cellular, signaling and repertoire changes will enable us to select and monitor proper therapy in patients with PIDD.

• Klíčová slova
• sekvenování nové generace, Next generation sequencing, primární imunodeficience, dysregulace, dysregulation, signalizace, imunofenotyp, immunophenotype, signaling, funkční testy, functional assays, repertoár receptorů lymfocytů, lymphocyte receptor repertoire, autoinflamatorní projevy, monogenní poruchy, Primary Immunodeficiency Diseases, autoinflammation, monogenic errors,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

In 2022, we celebrated 200 years since the birth of Johann Gregor Mendel. Although his contributions to science went unrecognized during his lifetime, Mendel not only described the principles of monogenic inheritance but also pioneered the modern way of doing science based on precise experimental data acquisition and evaluation. Novel statistical and algorithmic approaches are now at the center of scientific work, showing that work that is considered marginal in one era can become a mainstream research approach in the next era. The onset of data-driven science caused a shift from hypothesis-testing to hypothesis-generating approaches in science. Mendel is remembered here as a promoter of this approach, and the benefits of big data and statistical approaches are discussed.

• MeSH
• genetika * MeSH
• imaginace * MeSH
• lidé MeSH
• promotorové oblasti (genetika) MeSH
• výzkumný projekt MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.

• MeSH
• lidé MeSH
• plíce MeSH
• protoonkogenní proteiny c-hck genetika   metabolismus   MeSH
• protoonkogenní proteiny genetika   MeSH
• skupina kinas odvozených od src-genu * genetika   MeSH
• vaskulitida * genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Maturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. CASE REPORT: A female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. CONCLUSION: Digenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.

• MeSH
• cystická onemocnění ledvin genetika   patologie   MeSH
• diabetes mellitus 2. typu genetika   patologie   MeSH
• dítě MeSH
• fenotyp MeSH
• hepatocytární jaderný faktor 1-alfa genetika   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• heterozygot MeSH
• lidé MeSH
• mutace MeSH
• nemoci ledvin genetika   patologie   MeSH
• uterus abnormality   MeSH
• vrozené poruchy tubulárního transportu genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic inherited kidney disease, affecting an estimated 600 000 individuals in Europe. The disease is characterized by age-dependent development of a multiple cysts in the kidneys, ultimately leading to end-stage renal failure and the need of renal replacement therapy in the majority of patients, typically by the fifth or sixth decade of life. The variable disease course, even within the same family, remains largely unexplained. Similarly, assessing disease severity and prognosis in an individual with ADPKD remains difficult. Epidemiological studies are limited due to the fragmentation of ADPKD research in Europe. METHODS: The EuroCYST initiative aims: (i) to harmonize and develop common standards for ADPKD research by starting a collaborative effort to build a network of ADPKD reference centres across Europe and (ii) to establish a multicentric observational cohort of ADPKD patients. This cohort will be used to study factors influencing the rate of disease progression, disease modifiers, disease stage-specific morbidity and mortality, health economic issues and to identify predictive disease progression markers. Overall, 1100 patients will be enrolled in 14 study sites across Europe. Patients will be prospectively followed for at least 3 years. Eligible patients will not have participated in a pharmaceutical clinical trial 1 year before enrollment, have clinically proven ADPKD, an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m(2) and above, and be able to provide written informed consent. The baseline visit will include a physical examination and collection of blood, urine and DNA for biomarker and genetic studies. In addition, all participants will be asked to complete questionnaires detailing self-reported health status, quality of life, socioeconomic status, health-care use and reproductive planning. All subjects will undergo annual follow-up. A magnetic resonance imaging (MRI) scan will be carried out at baseline, and patients are encouraged to undergo a second MRI at 3-year follow-up for qualitative and quantitative kidney and liver assessments. CONCLUSIONS: The ADPKD reference centre network across Europe and the observational cohort study will enable European ADPKD researchers to gain insights into the natural history, heterogeneity and associated complications of the disease as well as how it affects the lives of patients across Europe.

• MeSH
• biologické markery analýza   MeSH
• hodnoty glomerulární filtrace MeSH
• konziliární vyšetření a konzultace * MeSH
• lidé MeSH
• longitudinální studie MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• polycystické ledviny autozomálně dominantní patofyziologie   terapie   MeSH
• prognóza MeSH
• průzkumy a dotazníky MeSH
• standardní péče organizace a řízení   MeSH
• výzkumný projekt * MeSH
• zdravotní stav MeSH
• zdravotnické služby * MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

Neurotransmiterové poruchy jsou vzácná dědičná neurometabolická onemocnění vedoucí k primární poruše metabolismu neurotransmiterů a jejich transportu a receptorových funkcí. Na biochemické úrovni se dají diagnostikovat pouze a výhradně vyšetřením neurotransmiterů a/nebo jejich metabolitů v CSF. Neurologické postižení patří rovněž mezi klíčové klinické příznaky poruch mitochondriálního energetického metabolismu a vyšetření CSF přispívá k jejich diagnostice. Předmětem projektu bude optimalizovat metody (HPLC) stanovení hladin neurotransmiterů a jejich metabolitů v CSF u pacientů s neurometabolickým onemocněním. Budeme charakterizovat vztahy mezi profilem neurotransmiterů a dalších metabolitů v CSF a fenotypem pacientů s mitochondriálním onemocněním. Součástí projektu bude analýza zastoupení specifických proteinů v CSF u pacientů s mitochondriálním onemocněním.; The paediatric neurotransmitter disorders represent an enlarging group of neurological syndromes characterised by abnormalities of neurotransmitter synthesis and breakdown. The diagnosis of monogenic defects of neurotransmission is almost exclusively based on the quantitative determination of the neurotransmitters and/or their metabolites in CSF. Central nervous system belongs to the most affected organ also in mitochodriopathies and CSF investigations are important in their diagnostic process. The aimof the proposed project is to optimise methods (HPLC) for detection of neurotransmitters and their metabolites in CSF in patient with suspected neurometabolic disorders. We will characterise the relationship between neurotransmitters profile in CSF and clinical phenotype of patients with confirmed mitochondrial disorder. The part of the project will be analyses of specific proteins in CSF in patients with mitochondrial disorders.

• MeSH
• dítě MeSH
• mitochondriální nemoci diagnóza   MeSH
• nedostatek kyseliny listové diagnóza   MeSH
• neurotransmiterové látky MeSH
• vrozené poruchy metabolismu diagnóza   MeSH
• vysokoúčinná kapalinová chromatografie metody   využití   MeSH
• Check Tag
• dítě MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• neurologie
• genetika, lékařská genetika
• biochemie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Cystická fibróza (CF) je jedno z nejsystematičtěji studovaných dědičných, monogenních onemocnění, a přesto zůstává dodnes mnoho patofyziologických procesů neodhaleno. Snahou odborníků na celém světě je co nejpřesnější charakterizace molekulární patogeneze CF, aby bylo možno vyvinout moderní terapeutické postupy. Důsledkem dlouholetého výzkumu je stále delší a kvalitnější život nemocných. Významným trendem je v současnosti snaha spolupracovat na mezinárodní úrovni a tak sdílet nejnovější poznatky. Z tohoto důvodu specialisté z nejrůznějších oborů spolupracují v rámci tzv. kolaborativních projektů týkajících se všech aspektů této chronické nemoci, a to od základního výzkumu, přes klinické projevy onemocnění až po sociální problematiku. Článek shrnuje informace o českém zapojení do mezinárodních projektů zabývajících se CF.

Cystic fibrosis (CF) is one of the most systematically studied severe and chronic monogenic disorders. Despite this fact, many pathophysiological mechanisms still remain to be elucidated in order to assure customised therapeutic strategies. Experts from all over the world have been investigating this complex disorder in order to understand its complex pathophysiology. In this regard, high numbers of cases are necessary for valid clinical studies. Therefore, the current trend in CF research is focused on international cooperation. Investigators from around the world cooperate within international projects pertaining to all aspects of CF, i.e. starting from the study of the basic CFTR gene defect, through all types of CF clinical trials, including analysis of relevant psychosocial issues. This article summarizes Czech participation in international projects related to CF.

• MeSH
• cystická fibróza diagnóza   genetika   terapie   MeSH
• financování organizované MeSH
• kvalitativně upravené roky života MeSH
• výzkumný projekt MeSH
• Geografické názvy
• Česká republika MeSH
• Evropa MeSH